Our overall hypothesis is that there are identifiable genetic predispositions to the development of pancreatic cancer. Our overall translational goals are to develop a scientific evidence base to inform genetic counseling and risk assessment of familial pancreatic cancer patients, to identify genetic alterations that are specifically targetable therapeutically, and to identify those high risk relatives who would benefit most from future chemoprevention trials and efforts to screen for early, and therefore potentially curable, pancreatic neoplasia. The goals of this project are to characterize further the phenotype of familial pancreatic cancer, to identify pancreatic cancer susceptibility genes, and to use these discoveries to improve clinical risk assessment for patients and their families. To achieve these goals we will utilize the unique resource of the National Familial Pancreas Tumor Registry, with over 3,900 pancreatic cancer families to conduct detailed analysis of the pathology of both familial and sporadic pancreatic cancer as well as penetrance analysis for established pancreatic cancer genes and environmental risk factors that allow for gene by environment interaction. In addition, candidate genes identified through our ongoing whole genome and exome sequencing individuals from over 100 familial pancreatic cancer families will be evaluated to identify additional pancreatic cancer susceptibility genes. We anticipate that our project will not only identify new pancreatic cancer genes but also quantify the risk of pancreatic cancer associated with these genes translating these findings into the clinical setting.